Differentially expressed transcript isoforms associate with resistance to tuberculin skin test and interferon gamma...

Area of Science:

• Immunology
• Genetics
• Infectious Disease

Background:

• Understanding immune resistance to Mycobacterium tuberculosis (Mtb) infection is crucial for developing novel therapies.
• Previous gene-level analysis identified monocyte transcriptional responses linked to resistance (RSTR phenotype).

Purpose of the Study:

• To identify novel genes associated with the RSTR phenotype using transcript isoform analysis.
• To determine if isoform-specific differences in gene expression are obscured by gene-level analyses.

Main Methods:

• Monocytes from RSTR individuals and those with latent Mtb infection (LTBI) were analyzed.
• Cells were infected with Mtb or left unstimulated, followed by RNA isolation and sequencing.
• Differential transcript isoform analysis was employed to identify RSTR-associated gene expression.

Main Results:

• 81 differentially expressed transcripts (DETs) in 70 genes were identified (FDR <0.05) between RSTR and LTBI phenotypes.
• Most DETs (79) were found under Mtb-stimulated conditions.
• Novel DET genes, including PDE4A and ZEB2, showed higher expression in RSTR subjects, while ACSL4 and GAPDH had RSTR-associated transcript isoforms.

Conclusions:

• Transcript isoform analysis reveals associations with Mtb resistance (RSTR phenotype) missed by gene-level approaches.
• Findings highlight the importance of isoform-specific analysis for understanding complex immune responses.
• Further validation in RSTR cohorts and functional studies are needed to confirm the role of newly identified genes.